My goal in seeking a Mentored Research Scientist Development Award (K01) is to develop a career in translational HIV research, integrating basic scientific advances in the field of HIV/AIDS with the development of novel strategies to treat viral infection. As outlined in my research plan, I will focus on the antiviral activity and therapeutic potential of the APOBEC3 host factors, concentrating on the suppressive effect of APOBECS-mediated cytidine deaminase activity on HIV-1 and Hepatitis C virus (HCV) replication in vivo. My ultimate goal is to contribute to our understanding of viral pathogenesis and conceptualize new approaches to infectious disease management, by cultivating and applying my expertise in evolutionary biology, population genetics, and benchtop molecular virology. I will be training and conducting the proposed research in a distinguished and exceptional research environment. This environment will include the University of California San Francisco (UCSF) Department of Medicine, The J. David Gladstone Institute of Virology and Immunology, the San Francisco Veterans Affairs Medical Center (SFVAMC), and the Stanford University School of Medicine Genome Technology Center. This research proposal makes use of a fortuitous synchronicity associated with the treatment of HCV disease in HIV/HCV coinfected individuals. The current standard of treatment for HCV infection is combination therapy with ribavirin and the immunomodulatory cytokine interferon-a (IFN-a). Clinical studies demonstrate that IFN-a treatment results in a pronounced reduction in HIV-1 viral load in addition to its intended antiviral effect against HCV. A number of recent in vitro studies demonstrate that IFN-a treatment strongly induces the expression of the antiviral host factor APOBEC3. We propose to characterize the contribution of APOBEC3 activity to the observed suppression of HIV-1 and HCV viremia in an existing, extensively characterized cohort of HIV/HCV coinfected individuals undergoing IFN-a treatment at the UCSF Medical Center or SFVAMC. The objective of this study is to evaluate APOBEC3 activity as a foundation for novel antiviral treatment strategies, and is therefore directly relevant to public health and the clinical management of HIV and HCV infection. [unreadable] [unreadable] [unreadable]